Receptor tyrosine kinases (RTKs) from the epidermal growth factor (EGF) receptor, or ErbB, family have been implicated in several human cancers. They are the targets of anti-cancer therapies that are in use (such as Herceptin - currently in use as a breast cancer drug), or in development. Our focus is on understanding the details of ErbB receptor regulation by their growth factor ligands, which include EGF and the neuregulins. A thorough understanding of this process should provide new avenues for designing mechanism-based inhibitors of the ErbB receptors, which could lead to valuable new anti-cancer therapies. It is now well established that ligand-induced dimerization is the key initial step in ErbB receptor transmembrane signaling, and ErbB receptors form both homo- and hetero-oligomers upon ligand binding. Prior to ligand binding, ErbB receptor dimerization appears to be 'autoinhibited' by an intramolecular tether that buries the primary dimerization site in an intramolecular interaction. Ligand binding induces a conformational change that breaks this tether, exposing the dimerization site and thus promoting receptor activation. We propose an investigation of the mechanism by which ligand binding exposes the dimerization site. We will also determine whether this mechanism (specifically proposed for EGF receptor dimerization) can explain neuregulin-induced ErbB4 homodimerization, as well as ligand-induced hetero-oligomerization of ErbB receptors. Exploiting what we have learned for EGFR, we will also investigate the mechanism of EGFR inhibition in Drosophila by Argos, a secreted inhibitor that is closely related to other ErbB ligands. Our Specific Aims are: 1. To test the hypothesis that homodimerization of all ErbB receptors (except ErbB2) is autoinhibited by an intramolecular tether that is reversed upon ligand binding 2. To determine the structural basis for neuregulin-induced ErbB receptor homo- and hetero-dimerization. 3. To test the hypothesis that Argos, a secreted inhibitor of Drosophila EGFR, functions as an inverse EGFR agonist. By furthering our detailed understanding of ErbB receptor dimerization, and exploring the mechanism for receptor inhibition by Argos, the studies proposed here promise to provide new avenues for developing mechanism-based inhibitors of the human EGF receptor. [unreadable] [unreadable]